1. Field of Invention
This invention relates to methods and compositions for increasing arousal and alertness of patients in comatose states and for ameliorating such comatose states by the concomitant administration of a compound acting as a gamma-aminobutyric acid (GABA) agonist and a compound acting as an adenosine antagonist, or by the sole administration of a compound acting as an adenosine antagonist.
2. Prior Art
Coma is a state of unconsciousness that is a common and usually immediate sequel of trauma to the head. It is believed to occur because of traumatic damage to axons in the brainstem. These axons are known collectively as the reticular activating system(RAS). The axons project forward to essentially all the major subcortical and cortical brain structures from a diffuse network of cell bodies in the brainstem and thalamus. See Caronna, Rehabilitation of the Head Injured Adult (Eds. Rosenthal, et al.) 59-73, (1983), F. A. Davis, Philadelphia, publisher, and Adams, et al., Principles of Neurology, Fourth Edition, 275-290, (1989), McGraw-Hill, New York.
In mammals, the RAS, when stimulated, appears to produce and maintain a state of heightened arousal and attention to environmental stimuli. See Adams, et al., ibid. It is known that certain adenosine receptor antagonists such as caffeine and theophylline produce marked arousal in cats and rats, and to a lesser extent, in humans. See Yen-Koo, et al., Pharmacol. 25, 111-115, (1982) and Bridges, et al., Ann. Rep. Med. Chem. 23, 39-48, (1988). However, attempts to arouse or improve humans becoming comatose because of head trauma have been limited to administration of agonists or antagonists of the brain neurotransmittersystems for dopamine, acetylcholine, or endorphins, i.e., L-DOPA, levodopa-carbidopa, physostigmine, and naloxone. See Gualtieri, Brain Injury, 2, 101-129, (1988); Van Woerkom, et al., Eur. Neurol. , 21, 227-234, (1982) and Haig, et al. , Arch. Phys. Med. Rehab., 71, 1081-1083, (1990). The aforesaid attempts have generally failed to produce arousal in comatose patients.
There is thus a need for a means to successfully arouse patients who are comatose because of traumatic head injuries.